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Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy

Abstract

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation1. At least eight autosomal genes involved in idiopathic epilepsy have been identified2, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome–linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine3 and polyglutamine4 disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.

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Figure 1: Genomic location and expression pattern of ARX.
Figure 2: Mutations in ARX affecting polyA tracts.
Figure 3: ARX mutation 1058C→T (Pro353Leu).
Figure 4: ClustalW multiple-protein alignment of the human, mouse and zebrafish ARX orthologs.

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Acknowledgements

We thank the members of the families studied for participation, and S. McDonnell and C. Derwas for help with cell culture. P.S. was supported by the Unger-Vetlesen Medical Fund, Jersey, and the Research Council of Norway; M.M. was supported by a Benjamin Poulton Medical Research Scholarship and K.L. by the Adelaide Research Scholarship from Adelaide University. This work was supported by the National Health and Medical Research Council of Australia. P.S. is on leave from Department of Paediatrics, Rikshospitalet, 0027 Oslo, Norway.

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Correspondence to Jozef Gécz.

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Strømme, P., Mangelsdorf, M., Shaw, M. et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 30, 441–445 (2002). https://doi.org/10.1038/ng862

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